Restenosis persists as a major complication in the maintenance of vessel patency after percutaneous transluminal angioplasty in coronary (PTCA) and other vessels. Restenosis is a consequence of multiple factors, including vessel recoil, negative vascular remodeling, residual plaque burden, and neointimal hyperplasia. Neointimal hyperplasia reflects the migration and proliferation of vascular smooth muscle (VSM) cells with subsequent deposition of extracellular matrix components at the site of injury. Considerable evidence indicates that, in restenosis, growth factors stimulate the VSM cells to proliferate, resulting in a thickening of the tunica intima. Nearly 40% of all patients develop significant luminal narrowing within 6 months after angioplasty procedures. Consequently, despite the initial therapeutic benefits of angioplasty, within a few months after surgery, blood flow through the affected vessels can again become compromised. Conventional therapies, which include angiotensin-converting enzyme inhibitors, anticoagulants, and statins, are ineffective in preventing or reducing neointimal hyperplasia after stretch injury. Endovascular radiation therapy has shown some success in both animal and human trials, yet the long-term deleterious effects of this therapy on the artery have not been adequately evaluated.
Ceramide is a growth arresting metabolite of sphingomyelin, a major lipid component of the cell membrane. More specifically, ceramide is a complex lipid which can be found in the plasma membrane. It is produced by the breakdown of sphingomyelin by sphingomyelinases, a process which is enhanced during inflammatory cytokine (IL-1, TNF and CD 95 ligand) induced growth arrest and/or cell death. It appears that ceramide acts as a bioactive which can mediate vascular smooth muscle-growth arrest and/or apoptosis by the direct activation of certain kinases. It is hypothesized that direct and immediate delivery of a cell-permeable ceramide or analog via the balloon tip of an embolectomy catheter or chronic delivery via coating of a stent would reduce the VSM proliferation that is observed in restenosis after angioplasty.
It is known that ceramide inhibits VSM proliferation by activating c-jun N-terminal kinase (JNK) while suppressing extracellular signal regulated kinase (ERK) and protein kinase B (PKB) in vitro. Yet, the possibility that a cell-permeable ceramide could diminish VSM proliferation in vivo has until now not been tested. The use of catheters to open diseased arteries, body vessels or cavities is also known, as in e.g., U.S. Pat. No. 5,599,307, herein incorporated by reference. However, the prior art therapeutic devices themselves induce a significant amount of regrowth of VSM in the artery, which leads to secondary blockages or occlusions (i.e., restenosis).
The present invention relates to a system and device for preventing stenosis (narrowing) and/or restenosis (renarrowing) after an invasive procedure (e.g., vascular or surgical intervention) in a body vessel or cavity having an inner wall surface, the system comprising inserting a device coated with a growth-arresting, lipid derived, bioactive substance at a desired location along the inner wall surface of the body vessel or cavity. By delivering the substance directly and immediately to the site of action, subsequent regrowth of smooth muscle cells is prevented, thus overcoming the inflammatory response which occurs due to the body""s dealing with the original surgical intervention, e.g., angioplasty.
In a preferred embodiment, the present invention discloses a ceramide treatment which significantly reduces neointimal hyperplasia induced by balloon angioplasty in carotid arteries. It is demonstrated that ceramide ameliorates stenosis by decreasing the trauma-associated phosphorylation of extracellular signal regulated kinase (ERK) and protein kinase B (PKB). As described below, it has been demonstrated that the utility of cell-permeable ceramide is a novel therapy for reducing restenosis after balloon angioplasty.